During the last two decades many genes have been shown to cause autosomal dominant forms of early onset dementing illnesses. These rare disorders have provided enormous insight into the pathogenesis of more common variants of the same diseases. Several of the most promising new therapeutics are based on the A hypothesis, a hypothesis largely supported by the causative mechanisms of disease mutations in autosomal dominant families. As these putative therapeutics are tested in clinical trials there is a growing need to use familial Alzheimer disease (FAD) kindreds both to understand the natural history of the earliest clinical and preclinical phases of the disease and to test the efficacy of the therapeutics in a setting, where if the A hypothesis is correct, they should have a dramatic effect on prognosis. During the last funding cycle, DIAN has developed a network of sites and has begun to characterize a large series of FAD kindreds with known disease-causing mutations. The goal of the next funding period will be to continue longitudinal follow up of these kindreds to identify the earliest detectable changes associated with development of disease and to characterize the temporal series of events that occurs up to and including the diagnosis of symptomatic AD. The goal of the Genetics Core of the DIAN initiative is to provide genetic information and useful biological materials to the research community for the study of AD. We have already collected samples from 326 individuals and extracted DNA. We will initiate collection of an additional 50 new individuals during the next funding period. Since these individuals are part of FAD kindreds with known causative mutations we will screen each sample for the known mutation in that family and genotype all families for known disease modifying alleles such as APOE e4. In this renewal application we will also genotype all mutation carriers using an Exome Chip to identify novel genes modifying age at onset of biomarker changes/symptoms. Blood from each individual will be sent to the National Cell Repository for Alzheimer?s Disease (NCRAD) for banking in the cell repository. Currently NCRAD has immortalized cell lines on 326 indiivduals from 129 DIAN families. Under separate funding DIAN has also collected skin biopsies from 44 individuals representing 16 different mutations in APP, PSEN1 and PSEN2.